Modulation of diacylglycerol acyltransferase 1 expression

Abstract

Compounds, compositions and methods are provided for modulating the expression of diacylglycerol acyltransferase 1. The compositions comprise oligonucleotides, targeted to nucleic acid encoding diacylglycerol acyltransferase 1. Methods of using these compounds for modulation of diacylglycerol acyltransferase 1 expression and for diagnosis and treatment of disease associated with expression of diacylglycerol acyltransferase 1, such as obesity and obesity-related conditions, are provided.

1. A method of reducing glucose levels, free fatty acid levels or insulin levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of a compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the modified oligonucleotide is complementary to a diacylglycerol acyltransferase 1 nucleic acid (SEQ ID NO: 4), wherein the expression of diacylglycerol acyltransferase 1 is inhibited and wherein administering the compound to said animal reduces glucose levels, free fatty acid levels or insulin levels. 
     
     
       2. The method of  claim 1  wherein the animal is a human. 
     
     
       3. The method of  claim 1  wherein the glucose levels are plasma glucose levels or serum glucose levels. 
     
     
       4. The method of  claim 1  wherein the animal is a diabetic animal. 
     
     
       5. A method of delaying the onset of a disease or condition associated with diacylglycerol acyltransferase 1 by reducing glucose levels, free fatty acid levels or insulin levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of a compound comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides, wherein the modified oligonucleotide is complementary to a diacylglycerol acyltransferase 1 nucleic acid (SEQ ID NO: 4), wherein the expression of diacylglycerol acyltransferase 1 is inhibited and wherein administering the compound to said animal reduces glucose levels, free fatty acid levels or insulin levels. 
     
     
       6. The method of  claim 5  wherein the animal is a human. 
     
     
       7. The method of  claim 5  wherein the condition is an abnormal metabolic condition. 
     
     
       8. The method of  claim 7  wherein the abnormal metabolic condition is hyperlipidemia, diabetes or obesity. 
     
     
       9. The method of  claim 8  wherein the diabetes is Type 2 diabetes. 
     
     
       10. The method of  claim 1 , wherein administering the compound to said animal modulates cholesterol levels. 
     
     
       11. The method of  claim 10  wherein the animal is a human. 
     
     
       12. The method of  claim 10  wherein the cholesterol levels are plasma cholesterol levels or serum cholesterol levels. 
     
     
       13. The method of  claim 1 , wherein administering the compound to said animal lowers triglyceride levels. 
     
     
       14. The method of  claim 13  wherein the animal is a human. 
     
     
       15. The method of  claim 13  wherein the triglyceride levels are plasma triglyceride levels or serum triglyceride levels. 
     
     
       16. The method of  claim 1 , wherein administering the compound to said animal reduces serum glucose levels. 
     
     
       17. The method of  claim 1 , wherein administering the compound to said animal reduces diacylglyerol acyltransferase 1 levels. 
     
     
       18. The method of  claim 1 , wherein administering the compound to said animal reduces circulating insulin levels. 
     
     
       19. The method according to  claim 18 , wherein said reduction is sustained over at least 5 weeks. 
     
     
       20. The method of  claim 1 , wherein administering the compound to said animal decreases fasted serum insulin levels. 
     
     
       21. The method of  claim 1 , wherein administering the compound to said animal improves an animal's performance on glucose tolerance tests and insulin tolerance tests. 
     
     
       22. The method of  claim 1 , wherein administering the compound to said animal reduces circulating triglycerides. 
     
     
       23. The method of  claim 1 , wherein administering the compound to said animal reduces liver triglycerides. 
     
     
       24. The method of  claim 1 , wherein administering the compound to said animal reduces free fatty acids in the liver. 
     
     
       25. The method of  claim 1 , wherein the modified oligonucleotide consists of 12 to 50 linked nucleosides. 
     
     
       26. The method of  claim 1 , wherein the modified oligonucleotide consists of 15 to 30 linked nucleosides. 
     
     
       27. The method of  claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide. 
     
     
       28. The method of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to human diacylglycerol acyltransferase 1. 
     
     
       29. The method of  claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
       30. The method of  claim 1 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
       31. The method of  claim 1 , wherein at least one nucleoside comprises a modified sugar. 
     
     
       32. The method of  claim 31 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
       33. The method of  claim 31 , wherein at least one modified sugar is a 2′-O-methoxyethyl. 
     
     
       34. The method of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
       35. The method of  claim 1 , wherein said modified oligonucleotide is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein the internucleoside linkages are phosphorothioate, and all cytidine residues are 5-methylcytidines. 
     
     
       36. The method of  claim 1 , wherein glucose levels are reduced. 
     
     
       37. The method of  claim 1 , wherein free fatty acid levels are reduced. 
     
     
       38. The method of  claim 1 , wherein insulin levels are reduced. 
     
     
       39. The method of  claim 5 , wherein glucose levels are reduced. 
     
     
       40. The method of  claim 5 , wherein free fatty acid levels are reduced. 
     
     
       41. The method of  claim 5 , wherein insulin levels are reduced.